A variety of growth factors that impact survival and development of oligodendrocyte (OLG) lineage cells in vivo and in culture may affect the extent of degeneration or remyelination of oligodendrocytes (OLGs) in white matter disease (Gao, Gillig et al. 2000;Mason, Suzuki et al. 2001;Armstrong, Le et al. 2002;Murtie, Zhou et al. 2005). Our results suggest that one of these molecules is brain derived neurotrophic factor (BDNF). Work in our lab during the previous funding period indicates that BDNF, through the mediation of TrkB, influences proliferation and differentiation of OLG subpopulations in culture. In addition, BDNF +/- mice exhibit decreases in MBP+ myelin profiles and NG2+ progenitors that develop in the corpus callosum. Preliminary studies suggest that they also exhibit blunted increases in NG2 and reduced MBP in response to a cuprizone-elicited demyelinating lesion. Based on these results, we hypothesize that following a demyelinating lesion, BDNF, through the mediation of trkB, directly increases OLG progenitor proliferation and OLG differentiation, impacting OLG remyelination. In particular, we propose to 1) use BDNF +/- mice to examine the role of BDNF in increasing numbers of OLG progenitors and differentiation of OLG lineage cells in the cuprizone injury model, 2) investigate the therapeutic potential of BDNF by evaluating effects of exogenous BDNF on regenerating and damaged OLGs following a cuprizone lesion, 3) test the hypothesis that BDNF acts to enhance proliferation and differentiation, but not to influence survival, and that TrkB on OLG lineage cells mediates BDNF action. PUBLIC HEALTH RELEVANCE: In demyelinating diseases there is a loss of oligodendrocytes, cells that provide insulating sheaths to neurons. Studies of this application are designed to evaluate roles of the growth factor BDNF in promoting development, survival and function of oligodendrocyte lineage cells during and after a demyelinating lesion. This work may lead to the development of BDNF as a therapeutic agent and to the identification of potential candidate genes for geneticists to test as susceptibility loci for these devastating diseases.